Sparsentan. Dual Angiotensin II AT1 Receptor Blocker and Endothelin ETA Receptor Antagonist, Treatment of Focal Segmental Glomerulosclerosis, Treatment of IgA Nephropathy
Drugs of the Future – 2020
Mechanism of Protective Actions of Sparsentan in the Kidney: Lessons From Studies in Models of Chronic Kidney Disease
Journal article
Published on May 29, 2024
Contributors:
Kohan DE, Bedard PW, Jenkinson C et al.
Kohan DE, Bedard PW, Jenkinson C et al.
DOI:
10.1042/CS20240249
10.1042/CS20240249
Summary
Endothelin-1 (ET-1) and angiotensin II (Ang II)
ET-1 and Ang II are important disease mediators in chronic progressive kidney disease such as IgA nephropathy and focal segmental glomerulosclerosis (FSGS)1
ET-1 and Ang II are present throughout the kidney and are strongly implicated in renal pathophysiology1-3
They have similar functions within the kidney and contribute to actions such as vasoconstriction, inflammation, and cellular proliferation1,2,4
Together, ET-1 and Ang II upregulate each other and exert an additive effect, driving ongoing kidney damage1,5,6
ET-1 and Ang II are present throughout the kidney
Class and structure of sparsentan
Sparsentan is a Dual Endothelin Angiotensin Receptor Antagonist (DEARA), with nephroprotective effects1
The sparsentan molecule consists of1:
A moiety that inhibits the endothelin type A receptor (ETAR)
A moiety that inhibits the angiotensin II subtype 1 receptor (AT1R)
The molecular structure of sparsentan targets ETAR and AT1R
Protective effects of sparsentan
Sparsentan targets glomerular injury and slows kidney function decline through several protective effects1,7
Preclinical data support the direct cellular, and resulting structural, actions of sparsentan1*
| In IgA nephropathy | In FSGS |
|---|---|
| Anti-inflammatory8-11* | Podocyte-protective13,14* |
| Anti-proliferative8,9,11* | Glycocalyx-protective14* |
| Anti-fibrotic10,11* | Glomerular vasodilation13,14* |
| Anti-proteinuric12 | Anti-fibrotic13* |
| Anti-inflammatory15* | |
| Anti-proteinuric16,17 |
*These effects are based on pre-clinical animal modeling data.
Resources
Conclusions
Collectively, the protective effects of sparsentan contribute to nephroprotection in kidney disease1
- By blocking important disease mediators, ET-1 and Ang II, sparsentan, a DEARA, can reduce glomerular injury and help preserve kidney function1
Related Content
Sparsentan. Dual Angiotensin II AT1 Receptor Blocker and Endothelin ETA Receptor Antagonist, Treatment of Focal Segmental Glomerulosclerosis, Treatment of IgA Nephropathy
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Sparsentan: The First and Only Non-Immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy
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Footnotes
As of October 2024, sparsentan is not FDA approved for the treatment of FSGS.
Ang II, angiotensin II; AT1R, angiotensin II subtype 1 receptor; DEARA, Dual Endothelin Angiotensin Receptor Antagonist; ET-1, endothelin-1; ETAR, endothelin type A receptor; FSGS, focal segmental glomerulosclerosis; IgA, immunoglobulin A.
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MA-SP-24-0108 | April 2025